Process for the production of pyridine derivatives

ABSTRACT

Provided is a process for producing high-purity pyridine derivatives in a high yield at a low cost without causing pollution problems. Pyridine derivatives are produced by reacting 1,2,4-triazine compound with a vinyl carboxylate having a specific structure.

TECHNICAL FIELD

The present invention relates to a process capable of producing, at alow cost in a high yield, high-purity pyridine derivatives serving as animportant intermediate for the production of pharmaceuticals,agrichemicals, catalyst ligands, silver halide photosensitive materials,liquid crystals and electrophotography, and organic photosensitivematerials or dyes used in the field of organic electroluminescence.

BACKGROUND ART

A variety of production processes of substituted pyridines have beenreported. For example, reported is a process of condensing a pyridinecompound and the N-oxide of another pyridine compound under heating inthe presence of platinum-added Pd-C (Yakugaku Zasshi, 99(12), pp. 1176,1181(1976)). The production yield is however low in this process. Alsoreported is cross-coupling reaction (Japanese Patent Laid-Open No. Sho64-003169) making use of Grignard reaction, which is however accompaniedwith the such problems as difficulty in gaining or synthesizing apyridine iodide compound necessary for obtaining a Grignard reagent ofpyridines and necessity of special equipment.

In addition, proposed are Ullman condensation reaction of two pyridinehalide compounds (Khim. Geol. Nauk., pp. 114(1970) and a process ofcross-coupling a pyridine halide compound with a metal derivative in thepresence of a Pd catalyst. For example, reported are cross-coupling witha borane derivative (Chem. Pharm. Bull., 33(11), pp. 4755(1985),Heterocycles, 23(9), pp. 2375(1985)), cross-coupling with an alkyl tinderivative (Tetrahedron Lett., 33, pp. 2199(1992)) and cross-couplingwith a pyridine halide compound in the presence of an Ni catalyst(WO9852922).

For mass production, however, they involve many problems such as highcost of the catalyst or reagent employed for the reaction and necessityof special treatment for the metal waste. Moreover, existence of manybyproducts of these reactions makes separation difficult and a productpure enough to use as an intermediate for pharmaceuticals or electronmaterials have not yet been obtained.

A process for synthesizing pyridine derivatives from a 1,2,4-triazinecompound by using 2,5-norbornadiene is conventionally known (forexample, Tetrahedron Lett., 39, pp. 8817, 8821, 8825 (1988)).

Upon use for mass production, however, 2,5-norbornadiene is accompaniedwith many problems that a large excess, more specifically, at least 10equivalents is required relative to the amount of a substrate, reactionis not completed in a short time, it is expensive, it is so toxic thateven slight suction of it causes headaches, and it has a problem instable supply on an industrial scale.

A process for obtaining pyridine compounds by using 1,2,4-triazine andvinyl acetate is reported (Tetrahedron Lett., 59, pp. 5171(1969)), butits yield is low and in addition, a substrate usable for this process islimited to highly active 1,2,4-triazine having an alkoxycarbonyl groupat the 3,5,6-positions.

An object of the present invention is to provide a process for producinghigh-purity pyridine derivatives useful as an intermediate ofpharmaceuticals, agrichemicals or liquid crystals in a high yield and ata low cost, in which the process does not generate pollution problemsand can be carried out on an industrial scale.

DISCLOSURE OF THE INVENTION

According to the present invention, the below-described processes forproducing pyridine derivatives are provided and the above-describedobjet of the present invention is attained.

(1) A process for producing a pyridine derivative, which comprisesreacting a 1,2,4-triazine compound with a vinyl carboxylate representedby the following formula (I):

wherein R represents an alkyl group having at least 3 carbon atoms, asubstituted or unsubstituted aryl group or a substituted orunsubstituted heterocyclic residue.

(2) The process for producing a pyridine derivative according to theitem (1), wherein in the formula (I), R represents a alkyl group having7 to 17 carbon atoms.

(3) The process for producing a pyridine derivative according to theitem (1), wherein in the formula (I), R represents a substituted orunsubstituted phenyl group or a substituted or unsubstitutednitrogen-containing heterocyclic residue.

(4) The process for producing a pyridine derivative according to theitem (1), which comprises reacting a 1,2,4-triazine compound representedby the following formula (III) with a vinyl carboxylate represented bythe above-described formula (I):

wherein R1, R2 and R3 may be the same or different and each represents ahydrogen atom, an alkyl group, an aryl group, a heterocyclic residue, analkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, anarylsulfinyl group, an arylsulfonyl group, an alkoxy group, a phenoxygroup, an alkoxycarbonyl group or a phenoxycarbonyl group; R2 and R3 maybe coupled together to form a ring.

(5) The process for producing a pyridine derivative according to theitem (4), wherein in the formula (III), R1 represents a phenyl group ora nitrogen-containing heterocyclic residue.

(6) The process for producing a pyridine derivative according to theitem (1), wherein the vinyl carboxylate is used in an amount of 1.01 to20 moles per mole of the 1,2,4-triazine compound.

(7) The process for producing a pyridine derivative according to theitem (1), wherein the vinyl carboxylate is used in. an amount of 1.5 to5 moles per mole of the 1,2,4-triazine compound.

(8) The process for producing a pyridine derivative according to theitem (1), wherein a reaction solvent having a boiling point of 100° C.or greater is employed.

(9) The process for producing a pyridine derivative according to theitem (1), wherein a reaction solvent having a boiling point of 180 to250° C. is employed.

(10) A process for producing a pyridine derivative, which comprisesreacting a 1,2,4-triazine compound with a vinyl carboxylate derivativerepresented by the following formula (II):

wherein n represents an integer of 0 to 18.

(11) The process for producing a pyridine derivative according to theitem (10), wherein in the formula (II), n represents an integer of 3 to12.

(12) The process for producing a pyridine derivative according to theitem (10), which comprises reacting a 1,2,4-triazine compoundrepresented by the following formula (III) with the vinyl carboxylaterepresented by the above-described formula (II):

wherein R1, R2 and R3 may be the same or different and each represents ahydrogen atom, an alkyl group, an aryl group, a heterocyclic residue, analkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, anarylsulfinyl group, an arylsulfonyl group, an alkoxy group, a phenoxygroup, an alkoxycarbonyl group or a phenoxycarbonyl group; R2 and R3 maybe coupled together to form a ring.

(13) The process for producing a pyridine derivative according to theitem (12), wherein in the formula (III), R1 is a phenyl group or anitrogen-containing heterocyclic residue.

(14) The process for producing a pyridine derivative according to theitem (10), wherein the vinyl carboxylate is used in an amount of 0.505to 10 moles per mole of the 1,2,4-triazine compound.

(15) The process for producing a pyridine derivative according to theitem (10), wherein the vinyl carboxylate is used in an amount of 0.75 to2.5 moles per mole of the 1,2,4-triazine compound.

(16) The process for producing a pyridine derivative according to theitem (10), wherein a reaction solvent having a boiling point of 100° C.or greater is employed.

(17) The process for producing a pyridine derivative according to theitem (10), wherein a reaction solvent having a boiling point of 180 to250° C. is employed.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will hereinafter be described more specifically.

In the vinyl carboxylate represented by the formula (I) or (II), Rrepresents a linear, branched or cyclic alkyl group having at least 3carbon atoms, a substituted or unsubstituted aryl group or a substitutedor unsubstituted heterocyclic residue. As the substituent for the arylor heterocyclic residue, those having a Hammett σm substituentconstituent falling within a range of −0.21 to 0.39 are usable. They maybe monosubstituted or polysubstituted. When polysubstituted,substituents may be the same or different. Specific examples of thesubstituent having Hammett am falling within a range of −0.21 to 0.39include alkyl groups such as methyl and t-buytl, cycloalkyl groups suchas cyclopentyl and cyclohexyl, aryl groups such as phenyl and naphthyl,alkoxy groups such as methoxy and ethoxy, amino groups such as amino anddimethylamino, a nitro group, and halogen atoms such as chlorine atomand bromine atom.

As R, examples of the linear, branched or cyclic alkyl groups having atleast 3 carbon atoms, preferably at least 5 carbon atoms, morepreferably 7 to 17 carbon atoms include propyl, isopropyl, butyl,isobutyl, s-butyl, t-buytl, butyl, pentyl, cyclopentyl, isopentyl,neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, cyclohexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 1-ethyl-2-methyl-propyl, heptyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,3-dimethylpentyl,2,4-dimethylpentyl, 3,4-dimethylpentyl, 1,1-dimethylpentyl,2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl,2-ethyl-1-methyl-butyl, 1-ethyl-2-methyl-butyl, 1-ethyl-3-methylbutyl,1-ethyl-3-methylbutyl, 2-ethyl-3-methylbutyl, 1-ethyl-1-methylbutyl,2-ethyl-2-methylbutyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl,1,2,2-trimethylbutyl, 1,1,3-trimethylbutyl, 1,3,3,-trimethylbutyl,2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl, 1-isopropyl-2-methylpropyl,octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl,5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylexyl,4-ethylhexyl, 1-propylpentyl, 2-propylpentyl, 1-butylbutyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl,1,5-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,2,5-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl,4,5-dimethylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl,1,2,3-trimethylpentyl, 1,2,4-trimethylpentyl, 2,3,4-trimethylpentyl,2-ethyl-1-methylpentyl, 3-ethyl-1-methylpentyl, 1-ethyl-2-methylpentyl,3-ethyl-2-methylpentyl, 1-ethyl-3-methylpentyl, 2-ethyl-3-methylpentyl,1-ethyl-4-methylpentyl, 2-ethyl-1-methylpentyl, 1-ethyl-1-methylpentyl,2-ethyl-2-methylpentyl, 3-ethyl-3-methylpentyl, 1,2-diethylbutyl,1,1-diethylbutyl, 2,2-diethylbutyl, nonyl, isononyl, s-nonyl, t-nonyl,neononyl, decyl, isodecyl, s-decyl, t-decyl, neodecyl, undecyl,isoundecyl, s-undecyl, t-undecyl, neoundecyl, dodecane, isododecane,s-dodecane, t-dodecane, neododecane, tridecyl, isotridecyl, s-tridecyl,t-tridecyl, neotridecyl, tetradecyl, isotetradecyl, s-tetradecyl,t-tetradecyl, neotetradecyl, pentadecyl, isopentadecyl, s-pentadecyl,t-pentadecyl, neopentadecyl, hexadecyl, isohexadecyl, s-hexadecyl,t-hexadecyl, neohexadecyl, heptadecyl, isoheptadecyl, s-heptadecyl,t-heptadecyl, neoheptadecyl, octadecyl, isooctadecyl, s-octadecyl,t-octadecyl, neooctadecyl, nonadecyl, isononadecyl, s-nonadecyl,t-nonadecyl and neononadecyl.

Examples of the aryl group as R include phenyl, naphthyl, tolyl, xylyl,cumenyl, mesityl, dimethylaminophenyl, diphenylaminophenyl,methoxyphenyl, phenoxyphenyl, cyclohexylphenyl, nitrophenyl,chlorophenyl, bromophenyl, fluorophenyl, iodophenyl, trifluorophenyl,hydroxyphenyl, carboxyphenyl, methyloxycarbonylphenyl and cyanophenyl.

Examples of the heterocyclic residue as R include pyridyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, pyrrolyl, pyrazolyl, imidazolyl,thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,methylpyridyl, phenylpyridyl, nitropyridyl, chloropyridyl, bromopyridyl,methoxypyridyl, diphenylaminopyridyl, methylpyrazinyl, phenylpyrazinyl,nitropyrazinyl, chloropyrazinyl, bromopyrazinyl, methoxypyrazinyl anddiphenylaminopyrazinyl.

In the formula (II), n stands for an integer of 0 to 18, preferably 3 to12.

When, in the formula (I), R represents an alkyl group having 1 or 2carbon atoms, the reaction between the 1,2,4-triazine compound and vinylcarboxylate proceeds very slowly. Such an alkyl group is thereforeunsuited for the industrial production of pyridine derivatives.

In the formula (I), R preferably represents a C₇₋₁₇ alkyl group. Rrepresenting a substituted or unsubstituted phenyl group or asubstituted or unsubstituted nitrogen-containing heterocyclic residue isalso preferred.

Specific preferred examples of R include propyl, isopropyl, butyl,isobutyl, s-butyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl,t-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, cyclohexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl,3-ethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,3,4-dimethylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl,3,3-dimethylpentyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylexyl, 4-ethylhexyl,1-propylpentyl, 2-propylpentyl, 1-butylbutyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 1,4-dimethylhexyl, 1,5-dimethylhexyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,3,4-dimethylhexyl, 3,5-dimethylhexyl, 4,5-dimethylhexyl,1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 5,5-dimethylhexyl, 1,2-diethylbutyl,1,1-diethylbutyl, 2,2-diethylbutyl, nonyl, isononyl, s-nonyl, t-nonyl,neononyl, decyl, isodecyl, s-decyl, t-decyl, neodecyl, phenyl, naphthyl,tolyl, xylyl, cumenyl, mesityl, nitrophenyl, chlorophenyl, bromophenyl,fluorophenyl, iodophenyl, trifluorophenyl, cyanophenyl, pyridyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, pyrrolyl, pyrazolyl,imidazolyl, thienyl and furyl.

As the 1,2,4-triazine compound, 1,2,4-triazine compounds represented bythe following formula (III) are preferred.

wherein, R1, R2 and R3 may be the same or different and each representsa hydrogen atom, an alkyl group, an aryl group, a heterocyclic residue,an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, anarylsulfinyl group, an arylsulfonyl group, an alkoxy group, a phenoxygroup, an alkoxycarbonyl group or a phenoxycarbonyl group; R2 and R3 maybe coupled together to form a ring.

One embodiment of reacting the 1,2,4-triazine compound with the vinylcarboxylate will next be described specifically for detailed descriptionof the invention process. It should however be noted that the scope ofthe present invention is not limited to or by it.

The reaction between the 1,2,4-triazine compound (III) and the vinylcarboxylate proceeds in accordance with the below-described reactionscheme, whereby the corresponding pyridine derivative (a) is produced.

wherein, R has the same meaning as described above, n stands for aninteger of 0 to 18, preferably an integer of 3 to 12, and R1, R2 and R3have the same meanings as described above.

A detailed description will next be made of R1, R2 and R3 in theformulas (a) and (III).

As examples of the alkys group, linear or branched C₁₋₁₈ alkyl groupscan be mentioned. Preferred examples include C₁₋₄ alkyl groups such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl. Of these, a methyl group which can be introduced into acarboxylic acid or aldehyde is more preferred.

As the aryl group, substituted or unsubstituted phenyl groups, naphthylgroup, anthryl group and phenanthryl group can be given. Preferredexamples include substituted or unsubstituted phenyl groups and naphthylgroups, with substituted or unsubstituted phenyl groups being morepreferred.

As examples of the substituent for the substituted aryl group,substituents having a Hammett σm substituent constituent falling withina range of −0.21 to 0.39 can be mentioned. They may be monosubstitutedor polysubstituted. When polysubstituted, substituents may be the sameor different. Specific examples of the substituent having Hammett σmfalling within a range of −0.21 to 0.39 include alkyl groups such asmethyl and t-butyl, cycloalkyl groups such as cyclopentyl andcyclohexyl, aryl groups such as phenyl and naphthyl, alkoxy groups suchas methoxy and ethoxy, amino groups such as amino and dimethylamino,nitro group, and halogen atoms such as chlorine atom and bromine atom.

Specific examples of the heterocyclic residue include substituted orunsubstituted pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,pyrrolyl, pyrazolyl, imidazolyl, thienyl, furyl, thiazolyl,isothiazolyl, oxazolyl and isoxazolyl groups. Of these, preferred aresubstituted or unsubstituted pyridyl, pyrazinyl, pyrimidyl, quinolyl,isoquinolyl, pyrrolyl and pyrazolyl groups, with substituted orunsubstituted pyridyl, pyrazinyl, pyrimidyl, quinolyl and isoquinolylgroups being more preferred.

As examples of the substituent for the substituted heterocyclic residue,substituents having a Hammett σm substituent constituent falling withina range of −0.21 to 0.39 can be mentioned. They may be monosubstitutedor polysubstituted. When polysubstituted, substituents may be the sameor different. Specific examples of the substituent having Hammett δmfalling within a range of −0.21 to 0.39 include alkyl groups such asmethyl and t-buytl, cycloalkyl groups such as cyclopentyl andcyclohexyl, aryl groups such as phenyl and naphthyl, alkoxy groups suchas methoxy and ethoxy, amino groups such as amino and dimethylamino,nitro group, and halogen atoms such as chlorine atom and bromine atom.

Specific examples of the alkylthio group include linear or branchedC₁₋₁₈ alkylthio groups, preferably C₁₋₄ alkylthio groups such asmethylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio and tert-butylthio, more preferably methylthio andethylthio.

As examples of the alkylsulfinyl (—SOR) and alkylsulfonyl (—SO₂R)groups, alkylsulfinyl and alkylsulfonyl groups having similar alkylgroups to those of the alkylthio group can be given. Preferred aremethylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl groups.

As examples of the arylsulfinyl (—SOAr) group, arylsulfinyl groupshaving a substituted or unsubstituted aryl group can be given andpreferred are benzenesulfinyl and toluenesulfinyl groups.

As examples of the substituent for the substituted arylsulfinyl group,substituents having a Hammett σm substituent constituent falling withina range of −0.21 to 0.39 can be mentioned. They may be monosubstitutedor polysubstituted. When polysubstituted, substituents may be the sameor different. Specific examples of the substituent having Hammett σmfalling within a range of −0.21 to 0.39 include alkyl groups such asmethyl and t-butyl, cycloalkyl groups such as cyclopentyl andcyclohexyl, aryl groups such as phenyl and naphthyl, alkoxy groups suchas methoxy and ethoxy, amino groups such as amino and dimethylamino,nitro group, and halogen atoms such as chlorine atom and bromine atom.

As examples of the arylsulfonyl (—SO₂Ar) group, arylsulfonyl groupshaving a substituted or unsubstituted aryl group can be given andpreferred are benzenesulfonyl and toluenesulfonyl groups.

As examples of the substituent for the substituted arylsulfonyl group,substituents having a Hammett σm substituent constituent falling withina range of −0.21 to 0.39 can be mentioned. They may be monosubstitutedor polysubstituted. When polysubstituted, substituents may be the sameor different. Specific examples of the substituent having Hammett σmfalling within a range of −0.21 to 0.39 include alkyl groups such asmethyl and t-buytl, cycloalkyl groups such as cyclopentyl andcyclohexyl, aryl groups such as phenyl and naphthyl, alkoxy groups suchas methoxy and ethoxy, amino groups such as amino and dimethylamino,nitro group, and halogen atoms such as chlorine atom and bromine atom.

Specific examples of the alkoxy group include linear or branched C₁₋₁₈alkoxy groups. Preferred are C₁₋₄ alkoxy groups such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, withlinear C₁₋₄ alkoxy groups such as methoxy, ethoxy, propoxy and butoxybeing more preferred.

As the alkoxycarbonyl (—COOR) group, the alkoxycarbonyl groups havingthe above-described alkoxy group can be mentioned. Preferred aremethoxycarbonyl and ethoxycarbonyl groups.

In the formula (III), R1, R2 and R3 may be the same or different andpreferred examples include a hydrogen atom, an alkyl group, an arylgroup or a heterocyclic residue. As R1, alkyl, aryl and heterocyclicresidue are more preferred, with phenyl and nitrogen-containingheterocyclic residue being especially preferred.

It is preferred that R2 and R3 represent the same group.

The 1,2,4-triazine compound which is a starting substance of the presentinvention can be prepared in any one of the following processes (1) to(4).

(1) A process for obtaining a 1,2,4-triazine compound by reacting acyanoheterocyclic compound with a hydrazine and then reacting theamidrazone thus derived by the above reaction with a diketone(Tetrahedron Lett., 39, pp. 8817, 8821, 8825(1998)). A productionprocess of a 1,2,4-triazine compound by adding water to this reactionsystem has already been found (Japanese Patent Application No. Hei11-167308). One embodiment of it will be described next.

(2) A process for producing a 1,2,4-triazine compound through acyanoheterocyclic compound, carbamate and then, amidorazone (J. KoreanChem. Soc., 39(9), pp. 755(1995)). One embodiment of it will bedescribed next.

(3) A process for producing a 1,2,4-triazine compound by reacting anacid hydrazide and a diketone with ammonium acetate in an acetic acidsolvent (Tetrahedron, 1, pp. 103(1957)). One embodiment of it will nextbe described.

(4) A process for producing a 1,2,4-triazine compound by reacting anα-haloketone with an acid hydrazide (Tetrahedron, 33, pp. 1043(1977)).One embodiment of it will next be described.

The vinyl carboxylate of the formula (I) or (II) usable in the presentinvention can be prepared readily from a carboxylic acid, which containsan alkyl group having at least 3 carbon atoms, a substituted orunsubstituted aryl group or a substituted or unsubstituted heterocyclicresidue, by the process as described below, but the production processis not limited thereto. Such vinyl carboxylates are easily availablebecause various ones are put on the market. Commercially available onesmay be used as they are.

Examples of the production process of the above-described vinylcarboxylate include the direct vinylation process (J. Am. Chem. Soc.,69, pp. 2439(1947), J. Polymer. Sci., 1, pp. 207 (1951), Trans. FaradaySoc., 49, pp. 1108(1953), U.S. Pat. No. 2,992,246 (1961), EuropeanPolymer J., 4, pp. 373(1968)), the vinyl exchange process (J. Org.Chem., 25, pp. 623(1960), Makromol. Chem., 73, pp. 173(1964)), Makromol.Chem., 29, pp. 119(1959), J. Polymer Sci., 27, pp. 269(1958), KobunshiKagaku, 17, pp. 227(1960), J. Sci. Eng. Res. Indian Inst. Technol.Kharagpur, 4, pp. 265(1990)), and the Halcon process (J. Am. Chem. Soc.,81, pp. 2552(1959)).

Specific examples of the vinyl carboxylate include vinyl butyrate, vinylhexanoate, vinyl octanoate, vinyl decanoate, vinyl laurate, vinylmyristate, vinyl palmitate, vinyl stearate, vinylcyclohexanecarboxylate, vinyl pivalate, vinyl octylate, vinylmonochloroacetate, divinyl adipate, vinyl methacrylate, vinyl crotonate,vinyl sorbate, vinyl benzoate, vinyl cinnamate, vinyl neodecanoate,vinyl neononanoate, vinyl 4-t-butylbenzoate, vinyl trifluoroacetate,vinyl-2-pyridine carboxylate, vinyl nicotinate, vinyl isonicotinate,vinyl-2-floate, vinyl 2-thiophenecarboxylate and divinyl adipate.

Of these, preferred are vinyl butyrate, vinyl hexanoate, vinyloctanoate, vinyl decanoate, vinyl laurate, vinyl myristate, vinylpalmitate, vinyl cyclohexanecarboxylate, vinyl pivalate, vinyl octylate,vinyl benzoate, vinyl neodecanoate, vinyl neononanoate, vinyltrifluoroacetate, and divinyl adipate, with vinyl hexanoate, vinyloctanoate, vinyl decanoate, vinyl laurate, vinyl cyclohexanecarboxylate,vinyl octylate, vinyl benzoate, vinyl neodecanoate, vinyl neononanoate,and divinyl adipate being especially preferred because of their easyseparability after completion of the reaction.

There is no limitation imposed on the amount of the vinyl carboxylateinsofar as it is at least an equimolar amount relative to the1,2,4-triazine. The vinyl carboxylate of the formula (I) is usually usedin an amount ranging from 1.01 to 20 moles, preferably 1.2 to 10.0moles, more preferably 1.5 to 5.0 moles, each relative the1,2,4-triazine (1 mole). The vinyl carboxylate of the formula (II), onthe other hand, has two reaction sites in its molecule so that half theamount of the above case is sufficient for the progress of the reaction.Described specifically, the vinyl carboxylate of the formula (II) isusually employed in an amount ranging from 0.505 to 10 moles, preferably0.6 to 5.0 moles, more preferably 0.75 to 2.5 moles, each relative tothe 1,2,4-triazine (1 mole).

In the present invention, use of the reaction solvent is notindispensable, but preferred is a solvent having a boiling point of 100°C. or greater, more preferably 130 to 300° C., still more preferably 180to 250° C.

As the reaction solvent, aromatic compounds are preferred.

The followings are aromatic compounds having a boiling point of 100° C.or greater and usable as the reaction solvent.

(i) Aromatic Hydrocarbon Compounds

Toluene, xylene, diethylbenzene, diisopropylbenzene, ethylbenzene,propylbenzene, butylbenzene, 1-phenylhexane, chlorobenzene,dichlorobenzene, trichlorobenzene, bromobenzene, dibromobenzene,methoxybenzene, methoxyphenol, dimethoxybenzene, nitrobenzene,1,4-cyclohexylbenzene, diphenylmethane, 1,2,3,4-tetrahydronaphthaleneand the like.

(ii) Aromatic Heterocyclic Compounds

2,4-Dichloropyrimidine, 2,3,5-trichloropyridine, quinoline, quinazoline,1,4-benzodioxane and the like.

(iii) Hydrogenated Aromatic Heterocyclic Compounds

1,2,3,4-Tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, 5,6,7,8-tetrahydroisoquinoline,1-phenylpiperidine, 1-phenylpiperazine, indoline, julolidine and thelike.

The followings are aliphatic compounds having a boiling point of 100° C.or greater and usable as a reaction solvent.

(iv) Saturated Aliphatic Compounds

Octane, nonane, decane, undecane, dodecane, tridecane, ethylcyclohexane,2-methyldodecane, 4-ethylundecane, tetradecane, pentadecane,3,3-dimethyltridecane, hexadecane, heptadecane,2-methyl-4-ethyltetradecane, and the like.

(v) Saturated Cyclic Aliphatic Compounds

Dicyclohexyl, decahydronaphthalene, dodecahydrofluorene and the like.

(vi) Saturated Heterocyclic Aliphatic Compounds1,3-Dimethyl-2-imidazolidinone (DMI), 1,4,7-trithiacyclononane,1,4,7-trithiacyclodecane, 1,4,7,10-tetraoxacyclododecane,1,4,7,10,13-pentaoxacyclopentadecane, 1,4,7-triazacyclononane and1,4,7,10-tetraazacyclododecane.

These solvents may be used either singly or in combination as a reactionsolvent.

Of the above-described reaction solvents, diethylbenzene,diisopropylbenzene, quinoline, nitrobenzene and1,3-dimethyl-2-imidazolidinone (DMI) are preferred, withdiisopropylbenzene and diethylbenzene being especially preferred. By theuse of such a solvent, the reaction time can be shortened and the targetcompound can be obtained in a high yield.

The reaction solvent is usually employed in an amount ranging from 1 to1000 ml, preferably 5 to 500 ml, more preferably 10 to 200 ml, relativeto 0.1 mole of the 1,2,4-triazine.

The reaction temperature usually ranges from 80 to 350° C., preferably120 to 300° C., more preferably 180 to 250° C. The disappearance of the1,2,4-triazine compound can usually be confirmed when reaction isconducted for 3 to 6 hours.

After completion of the reaction, dilute hydrochloric acid is added totransfer the target compound to the water layer, followed by separationinto layers. After the water layer is made basic, it is extracted into asolvent such as ethyl acetate or toluene. The solvent is thenconcentrated under reduced pressure. An alcohol or hexane is added tothe residue to crystallize the same, whereby a high-purity pyridinederivative is available. Purification may be conducted throughdistillation.

Specific preferred examples of the pyridine derivatives available by thepresent invention will next be shown as (A-1) to (D-11). It shouldhowever be borne in mind that the present invention is not limited to orby them.

EXAMPLES

The present invention will hereinafter be described by Examples infurther detail. It should however be borne in mind that the presentinvention is not limited to or by them. The purity was evaluated inaccordance with high-performance liquid chromatography (which willhereinafter be abbreviated as “HPLC”).

When the term “HPLC analysis” is used hereinafter, measurement isconducted under the below-described conditions. If any change, thechanged conditions are described specifically.

(Measuring Conditions of HPLC Analysis)

Column: YMC-A-312

UV detector wavelength: 254 nm

Eluent: acetonitrile/water=25/75, containing acetic acid andtriethylamine, each in an amount of 0.2 mass %, as a buffer.

Flow rate of the eluent: 1.0 ml/min

Synthesis Example 1 Synthesis of 3-(4-pyridyl)-1,2,4-triazine, aStarting Material

In a 2000-ml four-necked flask were charged 200 ml of water, 200.0 g(1.92 mole) of 4-cyanopyridine and 192.0 g (3.84 mole) of hydrazinemonohydrate. The mixture was reacted for 4 hours under stirring at 50°C. After confirmation of the disappearance of the raw material by HPLCanalysis, 400 ml of toluene was added and excessive hydrazinemonohydrate was distilled off. This operation was conducted again. Tothe residue were successively added 800 ml of water and 278.4 g (1.92mole) of a 40% aqueous glyoxal solution. The mixture was reacted for 2hours at an external temperature of 100° C. After completion of thereaction, the reaction mixture was cooled to 5° C., whereby 222.4 g(yield: 85.2%) of the target compound was obtained as pale yellowcrystals.

Example 1 Synthesis of 2,4′-dipyridyl (A-1)

In the next place, 45 ml of diisopropylbenzene, 25.0 g (0.158 mole) ofthe 3-(4-pyridyl)-1,2,4-triazine synthesized in Synthesis Example 1 and60.1 g (0.316 mole) of vinyl n-decanoate were charged in a 500-mlfour-necked flask. The resulting mixture was reacted under stirring at210° C. for 2 hours. After confirmation of the disappearance of the rawmaterial by HPLC, the reaction mixture was diluted with 100 ml oftoluene and made acidic with 180 ml of 1 mole/l hydrochloric acid,followed by separation into layers. The resulting water layer was washedwith 90 ml of toluene. This operation was conducted again. After theaqueous layer was made basic with 50 ml of 9 mole/l aqueous sodiumhydroxide solution, it was extracted into 120 ml of toluene. The solventwas then distilled off under reduced pressure and the residue wascrystallized from hexane, whereby 22.4 g (yield: 90.7%) of the targetproduct was obtained as pale yellow crystals. As a result of HPLCanalysis, the product was found to have a purity of 99.3%. Meltingpoint: 60 to 62° C.

Examples 2 to 7

In a similar manner to Example 1 except for the use of the vinylcarboxylate as shown in Table 1 instead of vinyl n-decanoate,2,4′-dipyridyl (A-1) was synthesized and its purity as measured by HPLCas well as its yield were evaluated.

Comparative Examples 1 and 2

In a similar manner to Example 1 except for the use of the vinylcarboxylate as shown in Table 1 instead of vinyl n-decanoate, synthesiswas conducted.

Comparative Example 3

In a 500-ml four-necked flask were charged 145 ml of xylene, 25.0 g(0.158 mole) of 3-(4-pyridyl)-1,2,4-triazine and 146 g (1.58 mole) of2,5-norbornadiene. The resulting mixture was reacted under reflux for 4hours. After completion of the reaction, excessive 2,5-norbornadiene andxylene were distilled off under reduced pressure. The residue wascrystallized from hexane, whereby 19.8 g (yield: 80.0%) of the targetproduct was obtained as pale yellow crystals. As a result of HPLCanalysis, its purity was found to be 99.2%.

Comparative Examples 4 and 5

In an autoclave were charged 45 ml of diisopropylbenzene, 25.0 g (0.158mole) of 3-(4-pyridyl) -1,2,4-triazine and 60.1 g (0.316 mole) of vinylacetate. The resulting mixture was reacted for each of 10 hours(Comparative Example 4) and 72 hours (Comparative Example 5) at 210° C.under stirring. At that time, the inner pressure increased to 1010 kPa.The above-described results are shown in Table 1.

TABLE 1 Reacti on To be reacted time Yield Purity with (h) (%) (%)Remarks Example Vinyl n- 2 90.7 99.3 1 decanoate Example Vinyl n- 3 90.799.2 2 octanoate Example Vinyl n- 16 90.4 99.2 3 hexanoate Example Vinylbenzoate 6 88.9 98.9 4 Example Vinyl 3 91.4 99.0 5 neononanoate ExampleVinyl pivalate 48 87.8 98.8 6 Example Vinyl n- 42 88.6 98.5 7 butyrateExample Vinyl 2- 6 88.8 99.0 8 pyridine- carboxylate Example Divinyl 291.5 99.0 9 adipate Example Vinyl 2 90.1 99.1 10 palmitate Comp. Vinylacetate 72 9.2 — Reaction Ex. 1 was not completed Comp. Vinyl 72 15.2 —Reaction Ex. 2 propionate was not completed Comp. 2,5- 4 80.0 99.2 Ex. 3Norbornadiene Comp. Vinyl acetate 10 10.0 — Reaction Ex. 4 (reaction inwas not Autoclave) completed Comp. Vinyl acetate 72 10.4 — Reaction Ex.5 (reaction in was not autoclave) completed

From the results as shown in Table 1, it has been revealed that:

By the process (Examples 1 to 10) according to the present invention,2,4′-dipyridyl (A-1) can be synthesized in a high purity and a highyield.

The reaction is not completed in Comparative Examples 1 and 2 whereinthe vinyl carboxylate of the formula (I) has carbon atoms as less as 1or 2. Neither is the case in Comparative Example 4 and 5 wherein thereaction is conducted in an autoclave under pressure. Even if the posttreatment is conducted while the reaction is not completed, separationusing an acid or base does not proceed smoothly, resulting in a drop ina yield and purity.

In Comparative Example 3, the conventional process by reacting a1,2,4-triazine compound with 2,5-norbornadiene was employed. The amountof 2,5-norbornadiene necessary for this reaction is at least 10equivalents relative to 3-(4-pyridyl)-1,2,4-triazine. Necessity of alarge amount of 2,5-norbornadiene and in addition, its expensivenessmarkedly raise the production cost compared with the invention process.

Examples 11 to 20

In a similar manner to Example 1 except for the use of the triazinederivatives as described below in Tables 2 and 3 instead of3-(4-pyridyl)-1,2,4-triazine, pyridine derivatives were synthesized.After reaction for 3 hours in Examples 15, 16 and 19, and for 2 hours inthe other Examples, the products were evaluated for their yields and,based on HPLC, their purities.

TABLE 2 HPLC Triazine Pyridine Yield Content derivative derivative (%)(%) Ex. 11

89.8 99.1 Ex. 12

93.3 99.5 Ex. 13

88.7 99.0 Ex. 14

89.4 99.3 Ex. 15

90.2 99.1 Ex. 16

90.8 98.9

TABLE 3 HPLC Triazine Pyridine Yield content derivative derivative (%)(%) Ex. 17

89.5 99.2 Ex. 18

92.9 99.3 Ex. 19

85.7 98.8 Ex. 20

90.0 99.0

As is apparent from Tables 2 and 3, pyridine derivatives can besynthesized in a high yield and high purity according to the inventionprocess.

<Industrial Applicability>

According to the process of the present invention, high-purity pyridinederivatives useful as an intermediate for pharmaceuticals,agrichemicals, catalyst ligands, silver halide photosensitive materials,liquid crystals and electrophotography, and for organic photosensitivematerials and dyes in the field of organic electroluminescence can beproduced in a high yield at a low cost. This process is free frompollution problems because no organic metal is used. Accordingly, theprocess of the present invention for producing pyridine derivatives hasmarkedly high utility from the industrial viewpoint.

What is claimed is:
 1. A process for producing a pyridine derivative,which comprises reacting a 1,2,4-triazine compound with a vinylcarboxylate represented by the following formula (I):

wherein R represents an alkyl group having at least 3 carbon atoms, asubstituted or unsubstituted aryl group or a substituted orunsubstituted heterocyclic residue.
 2. The process for producing apyridine derivative according to claim 1, wherein in the formula (I), Rrepresents a alkyl group having 7 to 17 carbon atoms.
 3. The process forproducing a pyridine derivative according to claim 1, wherein in theformula (I), R represents a substituted or unsubstituted phenyl group ora substituted or unsubstituted nitrogen-containing heterocyclic residue.4. The process for producing a pyridine derivative according to claim 1,which comprises reacting a 1,2,4-triazine compound represented by thefollowing formula (III) with a vinyl carboxylate represented by theabove-described formula (I):

wherein R1, R2 and R3 may be the same or different and each represents ahydrogen atom, an alkyl group, an aryl group, a heterocyclic residue, analkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, anarylsulfinyl group, an arylsulfonyl group, an alkoxy group, a phenoxygroup, an alkoxycarbonyl group or a phenoxycarbonyl group; R2 and R3 maybe coupled together to form a ring.
 5. The process for producing apyridine derivative according to claim 4, wherein in the formula (III),R1 represents a phenyl group or a nitrogen-containing heterocyclicresidue.
 6. The process for producing a pyridine derivative according toclaim 1, wherein the vinyl carboxylate is used in an amount of 1.01 to20 moles per mole of the 1,2,4-triazine compound.
 7. The process forproducing a pyridine derivative according to claim 1, wherein the vinylcarboxylate is used in an amount of 1.5 to 5 moles per mole of the1,2,4-triazine compound.
 8. The process for producing a pyridinederivative according to claim 1, wherein a reaction solvent having aboiling point of 100° C. or greater is employed.
 9. The process forproducing a pyridine derivative according to claim 1, wherein a reactionsolvent having a boiling point of 180 to 250° C. is employed.
 10. Aprocess for producing a pyridine derivative, which comprises reacting a1,2,4-triazine compound with a vinyl carboxylate derivative representedby the following formula (II):

wherein n represents an integer of 0 to
 18. 11. The process forproducing a pyridine derivative according to claim 10, wherein in theformula (II), n represents an integer of 3 to
 12. 12. The process forproducing a pyridine derivative according to claim 10, which comprisesreacting a 1,2,4-triazine compound represented by the following formula(III) with the vinyl carboxylate represented by the above-describedformula (II):

wherein R1, R2 and R3 may be the same or different and each represents ahydrogen atom, an alkyl group, an aryl group, a heterocyclic residue, analkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, anarylsulfinyl group, an arylsulfonyl group, an alkoxy group, a phenoxygroup, an alkoxycarbonyl group or a phenoxycarbonyl group; R2 and R3 maybe coupled together to form a ring.
 13. The process for producing apyridine derivative according to claim 12, wherein in the formula (III),R1 is a phenyl group or a nitrogen-containing heterocyclic residue. 14.The process for producing a pyridine derivative according to claim 10,wherein the vinyl carboxylate is used in an amount of 0.505 to 10 molesper mole of the 1,2,4-triazine compound.
 15. The process for producing apyridine derivative according to claim 10, wherein the vinyl carboxylateis used in an amount of 0.75 to 2.5 moles per mole of the 1,2,4-triazinecompound.
 16. The process for producing a pyridine derivative accordingto claim 10, wherein a reaction solvent having a boiling point of 100°C. or greater is employed.
 17. The process for producing a pyridinederivative according to claim 10, wherein a reaction solvent having aboiling point of 180 to 250° C. is employed.